SUMMARY / ABSTRACT Comorbid metabolic conditions of stroke, including obesity and diabetes, worsen stroke injury and reduce the capacity for stroke recovery. Given that stroke and these comorbid metabolic conditions are highly prevalent, the goal of this project is to understand how their interactions mechanistically affect the corticospinal motor system using high fat diet (HFD) as a model of metabolic disruption. In preliminary testing, HFD profoundly worsens behavioral motor recovery after experimental stroke. HFD and experimental stroke also cause an abnormal and profound emergence of lower extremity motor commands in areas of motor cortex that show little of these commands in otherwise healthy conditions or with experimental stroke injury and control diet. These abnormal lower extremity motor commands appear to be mechanistically due to increased synaptic signaling within the corticospinal system at connections that have not been well identified in this pathway. Volitional skilled motor control of the extremities is primarily achieved by the corticospinal tract and this pathway is often damaged by stroke resulting in severe disability. The canonical view of the corticospinal tract is that it is a synaptic circuit, from layer 5 pyramidal cells (L5PCs) in motor cortex, to spinal motor neurons that themselves signal skeletal muscle (CST= L5PCs? spinal motor neurons? skeletal muscle). L5PCs that project to cervical spinal cord (cervical-projecting) are thought to control upper extremity function whereas L5PCs that project to lumbar spinal cord (lumbar-projecting) are thought to control lower extremity function. What is less known is whether single L5PCs can innervate cervical and lumbar levels of spinal cord and thus contribute motor control to upper and lower extremities. Similarly, it is recognized that L5PCs synapse on one-another (L5PCs?L5PCs) however it is not known whether this is true between cervical-projecting L5PCs and lumbar-projecting L5PCs during stroke recovery. Experiments here will test these seldom studied connections of the corticospinal system because they may underpin the abnormal emergence of lower extremity motor commands that arise when HFD is combined with experimental stroke. To investigate these hypotheses, we propose 3 aims: Aim 1. Determine whether distribution and in vivo signaling of cervical- and lumbar-projecting L5PCs can support abnormal emergence of hindlimb motor commands in anterior motor cortex when HFD is combined with experimental stroke. Aim 2. Test whether physiology of cervical- and lumbar-projecting L5PCs can support abnormal emergence of hindlimb motor commands in anterior motor cortex when HFD is combined with experimental stroke. Aim 3. Test timing, duration and persistence of HFD to exacerbate upper and lower extremity deficits after experimental stroke injury. This proposal aims to determine the corticospinal circuits responsible for this abnormal plasticity of lower extremity motor control in order to guide its future targeted treatment as a novel therapy for stroke recovery in the context of clinically-relevant comorbid metabolic conditions.